Assessing the impact of dose on infection and vaccination outcomes

Slides: https://www.andreashandel.com/presentations/

Andreas Handel

2025-04-25

Talk Overview

  • Introduction
  • Role of dose for infections
  • Role of dose for vaccines
  • More stuff

Introduction

What we (maybe) know

  • Inoculum dose is an important determinant of infection and vaccination outcomes.
  • For infection, higher dose is often associated with greater risk of infection (ID50) and more severe outcomes (LD50).
  • For vaccines, higher dose is assumed to increase both immunogenicity/efficacy and side effects (morbidity).

Influenza infection in humans

Teunis et al. 2010 Epidemics

Norovirus infection in humans

Teunis et al. 2020 Epidemics

Pasteuria ramosa infections of Daphnia magna

Ben-Ami, Ebert, Regoes. 2010 Am Nat

Mostly open questions

  • If infection occurs what is the impact of dose on outcomes?
    • Pathogen kinetics and shedding/transmissibility
    • Symptoms/disease severity
    • Immune response, protective immunity
  • How exactly does dose impact vaccination outcomes?
    • Efficacy
    • Side effects/morbidity
  • What mechanisms of interactions between pathogen/antigen and host produce observed outcomes?

Viral infection kinetics

Virus load for different infections.

Li & Handel 2014 JTB

Viral kinetics

Viral kinetics modeling

\[ \begin{aligned} \textrm{Uninfected cells} \qquad \dot{U} & = - bUV \\ \textrm{Infected cells} \qquad \dot{I} & = bUV - d_I I - k_M M I - k_T T I\\ \textrm{Virus} \qquad \dot{V} & = pI - d_V V \\ \textrm{Macrophages} \qquad \dot{F} & = (s + g_V)(M^* - M - \alpha k_M M I) - d_M M \\ \textrm{T cells} \qquad \dot{T} & = \frac{r_T T V}{V + h_V} - d_T T \\ \end{aligned} \]

Viral kinetics modeling

With the right types of immune response terms in the models, one can capture patterns seen in the data.

Impact of dose following human norovirus infections

  • 6/7/6 individuals experimentally infected at low/medium/high dose.
  • Followed for 96h in facility, up to 91 days at home.
  • Tracking of virus, symptoms and antibodies.
  • Hierarchical/mixed-effects Bayesian statistical models to quantify impact of dose.

Ge et al 2023 EID

Virus load after norovirus infection

Virus load after norovirus infection

Dose dependence of virus kinetics

Impact of dose on symptoms following norovirus infection

Impact of dose on antibodies following norovirus infection

Part 1 Summary

  • Given infection occurs, dose influences virus kinetics in some instances (e.g. ADV, IBV) and has little impact in other instances (e.g., norovirus).
  • Dose seems to have a minor impact on symptoms and antibody response for norovirus.
  • We need to further understand the mechanisms by which dose impacts outcomes.

Part 2 - Vaccines

Background

  • Amount of antigen in a vaccine is expected to impact immunogenicity/protection and side effects.
  • There might be non-monotone relations between dose and outcomes.
  • We don’t understand the mechanisms by which dose impacts outcomes.

Current approaches to dose choice

  • A few doses are explored in phase I/II trials, one is chosen for phase III and licensure.

Example of BioNTech/Pfizer COVID Vaccine

Claim: Knowing in more detail how dose impacts host response following vaccination might help optimize vaccines.

Live HPIV (vaccine) modeling

Handel et al 2018 PLoS Comp Bio

Modeling dose and immune response

Modeling dose and immune response

\[ \begin{aligned} \textrm{Uninfected cells} \qquad \dot{U} & = - bUV \\ \textrm{Infected cells} \qquad \dot{I} & = bUV - d_I I \\ \textrm{Dead cells} \qquad \dot{D} & = d_I I \\ \textrm{Virus} \qquad \dot{V} & = \frac{pI}{1+s_F F} - (d_V V + k^{'}_{A}A + b^{'} U)V\\ \textrm{Innate response} \qquad \dot{F} & = p_F - d_F F + \frac{g_F (F_{max} - F)V}{V+h_V} \\ \textrm{B cells} \qquad \dot{B} & = \frac{F V}{FV+h_F} g_B B \\ \textrm{Antibodies} \qquad \dot{A} & = r_A B - d_A A - k_{A}AV \\ \end{aligned} \]

Modeling dose and immune response

Dose for HPIV vaccine

Conceptual model suggests that protection (and morbidity) could be peaked.

Inactivated influenza vaccine kinetics

Model prediction for inactivated vaccine

See also: Rhodes et al 2016 Vaccine, Rhodes et al 2019 JTB

SD versus HD Influenza Vaccines

  • High-dose (HD) influenza vaccine leads to better protection compared to standard-dose (SD) vaccine for the virus strains contained in the vaccine.
  • Does HD also induce a better protective antibody response against other influenza strains?

SD versus HD vaccine study

Billings et al 2025 JID

“Raw” data - homologous responses

“Raw” data - heterologous responses

Antibodies after HD/SD vaccine

Antibody kinetics following norovirus vaccination

Data from a phase 2 clincial dose-finding study of a norovirus vaccine candidate. Work in progress.

Antibody kinetics following norovirus vaccination

Part 2 Summary

  • Models suggest the impact of dose could be non-monotone.
  • Dose seems to have an impact for broad induction of antibodies following influenza vaccination.
  • Dose seems to have inconsistent effects on antibodies following norovirus vaccination.
  • Modeling could lead to better choice of optimal dose for vaccines - eventually?

Other stuff

R packages to make modeling easier I

For teaching (stable):

R packages to make modeling easier II

For research (WIP):

Online modeling/analysis courses

Acknowledgements

  • Collaborators
    • Prior work: See published papers
    • Ongoing work: Zane Billings, Murphy John, Yang Ge, Ye Shen, Ted Ross, Ben Lopman, Katia Koelle, Robert Atmar, several others…
  • Funding
    • NIH

Questions?

https://phdcomics.com/

  • Slides: https://www.andreashandel.com/presentations/
  • Contact: https://www.andreashandel.com